title: Membrane driven spatial organization of GPCRs.
abstract: Spatial organization of G-protein coupled receptors (GPCRs) into dimers and higher order oligomers has been demonstrated in vitro and in vivo. The pharmacological readout was shown to depend on the specific interfaces, but why particular regions of the GPCR structure are involved, and how ligand-determined states change them remains unknown. Here we show why protein-membrane hydrophobic matching is attained upon oligomerization at specific interfaces from an analysis of coarse-grained molecular dynamics simulations of the spontaneous diffusion-interaction of the prototypical beta2-adrenergic (β2AR) receptors in a POPC lipid bilayer. The energy penalty from mismatch is significantly reduced in the spontaneously emerging oligomeric arrays, making the spatial organization of the GPCRs dependent on the pattern of mismatch in the monomer. This mismatch pattern is very different for β2AR compared to the highly homologous and structurally similar β1AR, consonant with experimentally observed oligomerization patterns of β2AR and β1AR. The results provide a mechanistic understanding of the structural context of oligomerization.
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10065, United States.
authors.forename: Sayan
authors.initials: S
authors.lastname: Mondal
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Johnston
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Khelashvili
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines / Q000737:chemistry*; D011487:Protein Conformation; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine